Atypical antipsychotic clozapine binds fibrinogen and affects fibrin formation

Clozapine is an atypical antipsychotic used for the treatment of schizophrenia. The prescribed target daily doses may reach 900 mg. Literature studies report a connection between clozapine usage and thrombosis development. Our in vitro study aimed to provide insight into molecular bases of this observation, investigating clozapine binding to fibrinogen, the main plasma protein involved in hemostasis. Fibrinogen/clozapine interaction was confirmed by protein fluorescence quenching, with an affinity constant of 1.7 × 105 M−1. Direct interactions did not affect the structure of fibrinogen, nor fibrinogen melting temperature. Clozapine binding affected fibrin formation by reducing coagulation speed and thickness of fibrin fibers suggesting that in the presence of clozapine, fibrinogen may acquire thrombogenic characteristics. Although no difference in fibrin gel porosity was detected, other factors present in the blood may act synergistically with altered fibrin formation to modify fibrin clot, thus increasing the risk for development of thrombosis in patients on clozapine treatment. ORAC and HORAC assays showed that clozapine reduced free radical-induced oxidation of fibrinogen. All observed effects of clozapine on fibrinogen are dose-dependent, with the effect on fibrin formation being more pronounced.This is the peer-reviewed version of the article: Gligorijević, N.; Vasović, T.; Lević, S. M.; Miljević, Č.; Nedić, O.; Nikolić, M. Atypical Antipsychotic Clozapine Binds Fibrinogen and Affects Fibrin Formation. International Journal of Biological Macromolecules 2020, 154, 142–149. [https://doi.org/10.1016/j.ijbiomac.2020.03.119

Antipsychotic clozapine binds catalase and preserves its activity in oxidative environment

Oxidative stress undoubtedly accompanies mental disorders, and the pleiotropic effects of atypical antipsychotics, recommended drugs in the treatment of psychosis, are not clarified at the molecular level. Catalase is one of the key enzymes of the primary antioxidant protection system. This work studied the binding of second-generation antipsychotic drug Clozapine to commercial bovine liver catalase. Using various spectroscopic methods under simulated physiological conditions, we found moderate binding affinity of clozapine for catalase (Ka ~ 2x105 M-1), the binding influenced the secondary and tertiary structure of protein (according to UV-VIS and CD spectroscopy) and it managed to slightly increase its thermal stability. In AAPH induced oxidation experiments, we found that clozapine efficiently protects catalase from free-radicals oxidation and preserves its activity. Clozapine affects catalase activity in dose dependant manner, having no significant effect at lower concentrations but significantly inhibiting enzyme at saturating concentrations. In conclusion, our results indicate that the effect of direct binding of clozapine to catalase can be both beneficial and harmful and that this effect is dose dependent.The Biochemistry Global Summit, 25th IUBMB Congress, 46th FEBS Congress, 15th PABMB Congress, July 9-14, 2022, Lisbon, Portuga

Mean field approximation for noisy delay coupled excitable neurons

Mean field approximation of a large collection of FitzHugh-Nagumo excitable neurons with noise and all-to-all coupling with explicit time-delays, modelled by $N\gg 1$ stochastic delay-differential equations is derived. The resulting approximation contains only two deterministic delay-differential equations but provides excellent predictions concerning the stability and bifurcations of the averaged global variables of the exact large system.Comment: 15 pages, 3 figure

Atypical antipsychotic clozapine binds fibrinogen and affects fibrin formation

Clozapine is an atypical antipsychotic used for the treatment of schizophrenia. Prescribed daily doses of clozapine may reach over 900 mg/day. Some studies reported a connection between clozapine usage and the development of thrombosis. Our in vitro study aimed to provide insight into molecular bases of this observation, investigating clozapine binding to isolated fibrinogen, the main protein involved in hemostasis. Fibrinogen/clozapine interaction was confirmed by protein fluorescence quenching, with affinity constant calculated to be 1.7 9 105 M1 and the number of binding sites more than one. Direct interactions do not affect the structure of fibrinogen, as determined by UV-VIS spectrometry and Fourier-transform infrared spectroscopy, nor fibrinogen melting temperature, examined by fluorescence spectroscopy. However, clozapine binding affected fibrin formation, by reducing coagulation speed and thickness of fibrin fibers. This behavior suggests that in the presence of clozapine, fibrinogen may acquire thrombogenic characteristics. Although no difference in fibrin gel porosity was detected, other factors present in the blood may act synergistically with altered fibrin formation to modify fibrin clot, thus increasing the risk for development of thrombosis in individuals on clozapine treatment. By ORAC and HORAC antioxidant assays, we found that clozapine efficiently protects fibrinogen from free-radicals oxidation. Since the effect of clozapine on fibrin formation is dose-dependent, it seems that the dosage of the medication could be the main factor that determines if clozapine will have a more positive or negative effect on fibrinogen and coagulation process in vivo

A Metal Oxide Semiconductor ionizing radiation detector architecture with increased voltage sensitivity

A Metal Oxide Semiconductor (MOS) ionizing radiation detector architecture which senses trapped charge in the dielectric due to incident ionizing radiation is presented. The detector architecture increases output voltage signal as a function of trapped charge in the sensing dielectric in comparison with state of the art MOSFET (RADFET) technology. Numerical simulations were employed to help develop the device concept. It is shown that an improved voltage sensitivity is possible due to a reduction in the sensing capacitance which, unlike RADFET technology, is decoupled from the dielectric capacitance. An initial prototype of the detector has been fabricated in the silicon fabrication facility of Tyndall National Institute and irradiation experiments have been performed which confirm the improved voltage sensitivity versus commercial RADFET detectors. It is envisaged that further sensitivity increases may be possible by integrating dielectrics other than silicon dioxide.X JUBILEE International Conference on Radiation in Various Fields of Research : RAD 2022 (Spring Edition) : book of abstracts; June 13-17, 2022; Herceg Novi, Montenegr

Supplementary data for the article: Šunderić, M.; Vasović, T.; Milčić, M.; Miljević, Č.; Nedić, O.; Nikolić, M. R.; Gligorijević, N. Antipsychotic Clozapine Binding to Alpha-2-Macroglobulin Protects Interacting Partners against Oxidation and Preserves the Anti-Proteinase Activity of the Protein. International Journal of Biological Macromolecules 2021, 183, 502–512. https://doi.org/10.1016/j.ijbiomac.2021.04.155.

Supplementary material for: [https://doi.org/10.1016/j.ijbiomac.2021.04.155]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4538

Mean field approximation of two coupled populations of excitable units

The analysis on stability and bifurcations in the macroscopic dynamics exhibited by the system of two coupled large populations comprised of $N$ stochastic excitable units each is performed by studying an approximate system, obtained by replacing each population with the corresponding mean-field model. In the exact system, one has the units within an ensemble communicating via the time-delayed linear couplings, whereas the inter-ensemble terms involve the nonlinear time-delayed interaction mediated by the appropriate global variables. The aim is to demonstrate that the bifurcations affecting the stability of the stationary state of the original system, governed by a set of 4N stochastic delay-differential equations for the microscopic dynamics, can accurately be reproduced by a flow containing just four deterministic delay-differential equations which describe the evolution of the mean-field based variables. In particular, the considered issues include determining the parameter domains where the stationary state is stable, the scenarios for the onset and the time-delay induced suppression of the collective mode, as well as the parameter domains admitting bistability between the equilibrium and the oscillatory state. We show how analytically tractable bifurcations occurring in the approximate model can be used to identify the characteristic mechanisms by which the stationary state is destabilized under different system configurations, like those with symmetrical or asymmetrical inter-population couplings.Comment: 5 figure

Radiation Response of Two Types of Commercial RADFETs

V International Conference on Radiation in Various Fields of Research : RAD 2017 : book of abstracts; June 12-16, 2017; Budva, Montenegr

A design concept for radiation hardened RADFET readout system for space applications

Instruments for measuring the absorbed dose and dose rate under radiation exposure, known as radiation dosimeters, are indispensable in space missions. They are composed of radiation sensors that generate current or voltage response when exposed to ionizing radiation, and processing electronics for computing the absorbed dose and dose rate. Among a wide range of existing radiation sensors, the Radiation Sensitive Field Effect Transistors (RADFETs) have unique advantages for absorbed dose measurement, and a proven record of successful exploitation in space missions. It has been shown that the RADFETs may be also used for the dose rate monitoring. In that regard, we propose a unique design concept that supports the simultaneous operation of a single RADFET as absorbed dose and dose rate monitor. This enables to reduce the cost of implementation, since the need for other types of radiation sensors can be minimized or eliminated. For processing the RADFET's response we propose a readout system composed of analog signal conditioner (ASC) and a self-adaptive multiprocessing system-on-chip (MPSoC). The soft error rate of MPSoC is monitored in real time with embedded sensors, allowing the autonomous switching between three operating modes (high-performance, de-stress and fault-tolerant), according to the application requirements and radiation conditions

Biocorona formation of hen egg white proteins onto the surface of polystyrene and polyethylene terephthalate

Ovalbumin (OVA), a main protein of egg white, has characteristic structural fold of a serpin-family of proteins, propensity to fibril formation and stability to digestion. Microplastics (MPs) contaminating our food can interact with food proteins in the food matrix and during digestion. In this study adsorption of OVA to polystyrene (PS) (110 μm and 260 μm), polyethylene terephthalate (PET) (140 μm) MPs were investigated in acidic (pH 3) and neutral (pH 7) conditions. Formations of corona on MPs were investigated using isolated OVA and egg white protein extract comparatively. OVA adsorption depends on MPs size, polymer chemistry and pH, being highest in acidic pH and higher for PS. Adsorption of OVA to PS and PET reaches dynamic equilibrium after 4h resulting in disruption of tertiary structure and formation of hard and soft corona around MPs. Shorter fragments of OVA populate hard corona, while soft corona exclusively consist of full length OVA, albeit in its non-native conformation. The conformational changes resemble those induced by heat treatment with re-arrangement of α-β secondary structures. Structural changes are striking for the OVA in corona around MPs. Soft corona OVA preserves thermal and proteolytic stability, but loses ability to form fibrils upon heating. OVA is abundantly present in corona around MPs also in the presence of other egg white proteins. MPs contaminating food may bind and change structure and functional properties of main egg white protein